The gene for metabolic enzyme M1 is involved in catabolism of Drug P.
- The gene for metabolic enzyme M1 is involved in catabolism of Drug P. The structurally related drug Drug D is metabolized by a metabolic enzyme M2. Suppose that you wanted to initiate a genetics-based study to evaluate which patients would best be treated with Drug P, and for whom it would be better to use the related agent Drug D. In this question we will assume that ultrarapid metabolism (by either enzyme) confers a poor prognosis for response. Describe everything that you might do to complete this study*, such that it could be submitted to a scientific journal for review. Your answer should include (1) What is the specific goal of the study (i.e. state what specifically will be determined); (2) Description of several experiments (more than 1 and no more than 5), including how you would obtain data, and present their results. (3) Conclusions about pharmacogenetic guidance, based on your study. Aim to tie everything together in a logical way. (Would this be a pharmacogenetic or pharmacogenomic study?)
Note: “your answer does not literally need to be all the data that would typically be in a scientific published study. It might just be one important figure that captures the main goal of the project in several parts of the figure”.)
Question 2:
The disease malaria is caused by the microorganism Plasmodium falciparum and is transmitted by the Anopheles mosquito and is one of the 3 major infectious disease killers of the modern world. New therapies to target malaria are being actively investigated. One strategy is to target the insect that transmits the disease.
You decide to focus on the gene encoding heat shock protein 90 (hsp90) as an attractive new drug target. (1) Describe how you would go about cloning the gene for hsp90 from Anopheles. Include all steps necessary for a reader to evaluate whether your proposed procedure would be successful—but no need to include trivial issues such as, for example, how to make DNA segments that might use (one can just buy them) or how to sequence DNA (one can just have a company do it for you).
(2) How would you conclusively establish at the end of your procedure that the cloned gene was Hsp90?
(3) How could you use the cloned gene to improve human health through drug therapy?
Answers the (2) and (3) parts that will be scored as “outstanding” could be as short as one sentence.
(note please do not research hsp90, or malaria, or Plasmodium. For the purposes of this question, just assume that hsp90 is a very important gene, required for the growth and survival of the malaria parasite in the mosquito host)
The gene for metabolic enzyme M1 is involved in catabolism of Drug P.
Question 3:
Tasmanian devils (a dog-like creature) have recently begun to suffer from a disease that causes them to develop infectious transmissible facial tumors. The number of Tasmanian devils is dramatically declining because of this, and though there are still hundreds of thousands, there are worries that they may become extinct. (this part is accurate. What follows is an imagined (not real) scenario so don’t be searching for clues)
However, it has been observed that there is a relatively large population of Tasmanian devils in the western part of Tasmania with significant inherent resistance to the disease, suggesting that individuals within this local, geographically isolated population may share genetic features that render them less susceptible to infections that can produce the tumors.
(1) Describe how you would carry out a GWAS study to identify the gene(s) (gene variants) found in Tasmanian devils living in western Tasmania that confers resistance to infection to them. What would be one limitation that might be encountered in achieving an unambiguous discovery? (related to pharmacogenetic studies; please do not answer something like “they would be too difficult to catch” or “I would contract the disease”; I’m looking for a statement(s) like one might read in a scholarly journal relating to a pharmacogenetics study).
(2) Describe how this study in Tasmanian Devils might be applicable to human health and drug development.
Extra credit 5 points: Suggest how the discoveries made in part 1 or part 2 of this question might be applied to save the Tasmanian devil from extinction.
Question 4:
In a large-scale trial of agent A for pancreatic cancer in mice*, it was determined that ~20% of mice treated with the agent showed reduced or absent malignant cells, but the agent appeared to have no benefit in the other 80%. In addition, a significant number of deaths due to coronary incidents (CVD) was observed in the treated mouse cohort (10% affected) compared to the untreated control group (no CVD). (This would be considered an Adverse Unwanted Drug Side Effect (ADR)). (note: same frequency of CVD was observed in drug-treated responders and drug-treated non-responders)
Further studies determined that protein X expression varied significantly. Those mice below a threshold (roughly the lowest 20%) responded to agent A in most cases, whereas mice with normal amounts of protein X did not show pancreatic cancer remission. From a benefit/risk perspective, clinicians conclude that the drug cannot be used to treat all persons (too low efficacy, too high risk), but within the sub-population with low protein X expression the benefits may far outweigh the risk.
Describe test(s) that could be performed (in mice) to identify “patients”* who would benefit from treatment and should receive agent A. I trust you can appreciate there are two issues involved: improve response rate and reduce ADR. Describe in broad detail what would be done to (1) identify who should be treated (describe precisely, with details, exactly what screening you would recommend to be standard-of-care pre-treatment pharmacogenetic determination), and (2) how to establish patients who should not be treated because they were prone to the ADR. I am imagining there may be more than one test that is required. (As in part (1), don’t answer part (2) in 2-5 words; provide details of exactly what would be done, and how one would analyze and interpret the results)
The gene for metabolic enzyme M1 is involved in catabolism of Drug P.
